Cytomegalovirus Ebooks Catalog

How To Manage And Live With Herpes

By Pauline Banes on Fri, 02 Nov 2018

How To Manage And Live With Herpes Shows Herpes Sufferers How To Have Healthy, Happy Relationships Despite This Crippling Disease That Affects Millions Of New People Each Year. With This Simple-to-use Guide They Can Manage Herpes And Enjoy Love. Youre about to: Find out how to get rid of embarrassing sores and blisters and never suffer the embarrassment of looking like a zombie again. Discover how to keep those nasty outbreaks at bay with powerful natural remedies. Discover how to identify the 9 types of herpes and sleep better at night without fear of transmitting herpes. Understand why you have frequent herpes outbreaks. Re-invent your sex life and manage herpes simplex. Stop it from managing you! Learn about the one thing you Must know if you want to have 100% safe sex moving forward. Never feel guilty about infecting a partner again.

How To Manage And Live With Herpes Summary

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Cytomegalovirus latency depends on an interaction with hematopoietic cells in bone marrow and peripheral blood. The distribution of latent viral DNA and transcripts in these cells was investigated using methods based on polymerase chain reaction (PCR)-driven in situ hybridization (ISH) and reverse transcription (RT)-PCR-driven ISH. Using a conventional thermal cycler, latent viral DNA or transcripts were amplified within suspension cells. Amplified products were then detected by nonisotopic ISH on cells cytospun on glass microscope slides. During experimental latent infection of cultured granulocyte-macrophage progenitors, the viral genome was detected in more than 90 of cells. During natural infection, viral genomes were detected in 0.004 to 0.01 of mononuclear cells from granulocyte colony-stimulating factor mobilized peripheral blood or bone marrow from healthy seropositive donors. When evaluated by RT-PCR-ISH, only a small proportion of experimentally infected cells (approx 2 )...

Finally, Sgaramella, Borgo, Fenzo, Garofano, and Toso (2000) first investigated prospective memory performance in patients with herpes simplex encephalitis. Given that these patients are reported to exhibit impairments in retrospective memory and executive functioning, substantial deficits of the patients in prospective remembering were expected. Consistently, patients appeared to be severely impaired in executing time- and event-based prospective memory tasks however, no control group was included in the design.

Although most cases of post-transfusion cytomegalovirus (CMV) infection are subclinical, the syndrome of post-transfusion infectious mononucleosis-like illness is well recognized, especially after the transfusion of large amounts of blood. The infection is characterized by fever, splenomegaly and atypical lymphoid cells in the peripheral blood, with a negative Paul Bunnell test. The usually benign course of CMV infection in recipients has meant that there has been no necessity to screen all donors for evidence of past infection. However, immunosuppressed individuals are at great risk from potentially fatal pneumonitis or disseminated cytomegalovirus infection, and these recipients require special measures to prevent CMV transmission.

Acyclovir (25) is a potent and selective anti-herpes drug (Schaeffer et al., 1978) that could offer a means for topical treatment of herpes simplex virus (HSV) keratitis. However, the delivery characteristics of acyclovir are far from optimal, which can be attributed to its limited aqueous solubility (1.4 mg mL) and moderate lipophilicity (logP -1.47) (Bundgaard et al., 1991). Thus, acyclovir cannot be given as eye drops, which would be the most practical formulation for the treatment of ocular infection. The efficacy of 3 acyclovir eye ointment has been reported in the treatment of epithelial keratitis (Richards et al., 1983). Due to various side effects associated with the use of ointments in the eye, however, acyclovir has not been approved for the treatment of HSV keratitis in the United States. In addition, acyclovir ointment is not effective against stromal keratitis or when deeper tissues are involved (Sanitato et al., 1984). Prodrug strategies have been applied to improve...

Herpesviruses are disseminated widely in nature and infect most animal species. Eight herpesviruses have been isolated from humans so far Human herpesvirus 1 (HHV-1 Herpes simplex 1, HSV-1) HHV-2 (Herpes simplex 2, HSV-2) HHV-3 (Varicella-zoster virus, VZV) HHV-4 (Epstein Barr Virus, EBV) HHV-5 (Human cytomega-lovirus) and HHV-6, -7 and -8. Herpesviruses share a number of biological properties, including the ability to code for a large number of enzymes involved in nucleic acid metabolism, synthesis of viral DNA and capsid assembly take place in the nucleus, and the viral envelope is acquired during migration from the nucleus, production of infectious virus is accompanied by cell destruction, and the herpesviruses establish latent infection in the host. The herpesviruses affecting humans are probably the viruses that have been studied most extensively. Genital herpes, caused most frequently by HSV-2 but also by HSV-1, is the most relevant to the traveller. The herpes simplex viruses...

Reporter genes have also been engineered into viral vectors. The reporter gene can be used to track the type of cells the virus infects, the timing and duration of expression for viral genes (43), and viral latency (44). By linking viral promoter and enhancer elements to reporter genes in viral or plasmid DNA vectors, an increased understanding of the control of viral genes has been possible (45). This type of understanding has been applied to the development of genetically engineered reporter cell lines used for detection of virus, such as herpes simplex virus, in clinical samples (46)

Why do clinicians need to understand pharmacology when treating infections It could reasonably be argued that for the standard bacterial infection, prescribing of an appropriate antibiotic with little more than a rudimentary knowledge of pharmacology usually results in successful eradication. The same is alas not true of antiviral drugs. Unlike most bacteria, viruses utilise host cell mechanisms for their own replication and are as a general rule harder to treat. Drugs not only have to penetrate inside the cell and target these processes, but must also achieve this with minimum detriment to host cell metabolism. Toxicity is consequently increased. Many viruses (e.g. herpesviruses) have the capacity to undergo latency and are difficult to eradicate. Others such as hepatitis C produce chronic infection and require prolonged treatment. Therapeutic alternatives are more limited than for bacterial infection and pharmacological manipulation may be required to minimise toxicity or maximise...

Attention to the quality of data regarding causes of death could provide insight into the mechanisms of preterm birth as well as the causes of fetal and early neonatal deaths. This approach would require clinicians to vigorously search for causes of death whenever a fetal or early neonatal death occurs. Petersson et al. (2004) found that 11.5 percent of fetal deaths that would have been characterized as unexplained were due to infections with parvovirus, cytomegalovirus, or enterovirus. Other possible causes that should be explored include thrombophilias (e.g., Factor V Leiden), fetomaternal hemorrhage, chorioamnionitis (which would include pathologic examination of the placenta and the umbilical cord), uterine anomalies, umbilical cord or placental anomalies, toxin or drug exposures, and maternal illness (e.g., diabetes, hypertension with or without preeclampsia, thyroid disease, and autoimmune diseases) (Gardosi et al., 2005). Because the most common condition associated with fetal...

A CD4 + T cell number of 200 mm or over and any of the following conditions fungal diseases, including candidiasis, coccidioidomycosis, cryptococcosis, histop-lasmosis, isosporiasis Pneumocystis carinii pneumonia cryptosporidosis, or toxoplasmosis of the brain, bacterial diseases including pulmonary tuberculosis and other Mycobacterium species, recurrent Salmonella septicaemia viral diseases, including cytomegalovirus infection, HIV-related encephalopathy, HIV wasting syndrome, chronic ulcer or bronchitis due to herpes simplex, or progressive multifocal leucoencephalopathy malignant diseases such as invasive cervical carcinoma, Kaposi sarcoma, Burkitt lymphoma, primary lymphoma of the brain, or im-munoblastic lymphoma recurrent pneumonia due to any age.

Nitric oxide synthase (eNOS) in rats was associated with a reduction in acute pulmonary vasoconstriction 17 . We therefore reasoned that overexpression of a secreted and diffusible form of VEGF (VEGF165) in epithelial cells following adenoviral-mediated gene transfer may affect endothelial cell behavior and protect against pulmonary vascular remodeling during development of hypoxic pulmonary hypertension. To investigate this hypothesis, we used a previously described adenovirus vector containing an expression cassette with the cytomegalovirus (CMV) early intermediate promoter enhancer driving the human VEGF165 cDNA (Ad.VEGF) 24 .

In these studies, angiostatin delivery was achieved by a defective adenovirus expressing a secretable angiostatin K3 molecule driven by the cytomegalovirus promoter (Ad.K3) 29 . We first evaluated the efficiency of gene transfer in the lungs from mice with a single intratracheal instillation of the adenovirus by detecting the protein in bronchoalveolar lavage (BAL) fluid. We found that adenoviral-mediated lung overexpression of the angio-genesis inhibitor, angiostatin, aggravated development of hypoxic pulmonary hypertension in mice. Evidence for an activation of endogenous angiogenic processes in the lung during exposure to hypoxia was highly suggested by the observation that factor VIII endothelial cell immunostaining was increased in chronically hypoxic mice (Figure 2). This change was suppressed by pre-treatment with Ad-angiostatin, which also inhibited in vitro endothelial cell growth and migration 29 . Since treatment with Ad-angiostatin did not affect PA-SMCs function in vitro,...

Patients with recurrent oro-facial herpes simplex virus (HSV) frequently relate this to a psychostressful event. The nature of the HSV is such that active infection occurs with the loss of antiviral control. The HSV is latent within the sensory dorsal root ganglion until some stimulus precipitates an activation where the virus migrates down the sensory nerves to the skin. The stimulae can be as variable as fever, trauma, infection and stress. Studies in recurrent HSV (Biondi &amp Zannino, 1997) show that there is a shift from the Thl-mediated T-cell control to a more primitive Th2 humoral response. Essential in this mechanism is the neuroendocrine stimulus to HPA corticosteroid secretion. This was found to produce an HSV IgE response and a poor cell-mediated immunity to the virus. The humoral response allows reactivation of active virus whereas T-cell type 2 responses are essential for virus killing. Multifaceted cognitive-behavioural stress management reduced EBV capsid antigen and...

A large number of studies have consistently shown that emotionally arousing, particularly negative, stimuli-such as stories 92, 93 , pictures 94 , and words 95 -are better remembered than similar material without emotional value. Based on the fear-conditioning animal literature, it has been assumed that the amygdala plays a role in the enhancement of memory by emotion. Lesion studies with patients with unilateral temporal lobectomy (surgical treatment for intractable epilepsy) or selective bilateral lesions of the amygdala (Urbach-Wiethe disease or herpes simplex encephalitis) have largely confirmed this hypothesis. One of the first studies was performed by Markowitsch and colleagues with two patients, known as B.P. and C.P.,with Urbach-Wiethe disease 96 , presenting bilateral mineralization of the amygdala and deficits in emotional memory (B.P. less impaired than C.P.). Specifically, B.P. failed to show any memory enhancement for emotional words, whereas C.P. had a superior memory...

Esophageal perforations are rare in children, but the incidence is increasing as more diagnostic and therapeutic endoscopies are performed. Iatrogenic esophageal perforation is the cause in 33 -75 of cases (MARtiNEz et al. 2003). The incidence is low in upper endoscopy, and higher with rigid dilators. Esophageal perforations are more likely to occur if a foreign body has been present more than 24 h and caused pressure necrosis. Other etiologies are pill-induced, caustic damage, infectious, including candida, herpes and tuberculosis. Cervical esopha-geal perforation may result from penetrating trauma by objects in the mouth, including lollipops and pencils. Esophageal perforation is potentially life-threatening because it allows entry of bacteria and digestive enzymes into the pleural and subphrenic spaces and the mediastinum, causing sepsis. Perforation of the intraabdominal esophagus may lead to sepsis and shock.

After cloning of the cDNA for firefly luciferase, a new range of applications involving the use of the luciferase gene as a reporter gene appeared. Since then, the firefly luciferase gene has been extensively used to investigate transformation and transfection efficiencies in different cells, analysis of promoter activities, and location of gene expression, etc. 52-54 . Viral vectors such as adenovirus, HSV, vaccinia virus, etc., were labeled by inserting the firefly luciferase gene and were used to monitor their gene expression and dissemination in cells and tissues 55-58 . Regulation of gene expression of human cytomegalovirus (HCMV) and human immunodeficiency virus (HIV) in individual intact HeLa cells has been imaged using constructs with firefly luciferase gene downstream ofviral promoters 54 . The firefly luciferase gene has been expressed in several mammalian cell lines such as monkey kidney cells, Chinese hamster ovary cells, HeLa cells, and rat pituitary tumor cells 51-58 . A...

The firefly luciferase gene has been transiently and stably expressed in mammalian organisms for a variety of purposes 52-54, 61-64 . It has been used to follow up bacterial infections in model animals using Streptococcus, Salmonella, and Staphylococcus aureus strains and mycobacterial infections such as Mycobacterium tuberculosis 64-67 . Bioluminescent Candida albicans strains also have been engineered with the firefly luciferase gene to follow the course of infections in living mice models. Similar studies have been done using viral infections such as herpes (HSV) 57 and adenovirus 56 . Transgenic mice containing viral promoter fusions such as HTMLV have been developed and tested to study the range of tissues and cells that are capable of supporting viral expression. HIV infection can be followed by real-time imaging in mammalian cell cultures and in live animals. Assays for HIV using a plasmid that contains the firefly luciferase gene under the control of a viral promoter have been...

Here we list a number of physiological responses via mechanisms other than S-nitrosation. More precisely, processes for which S-nitrosation does not play a role or in which S-nitrosation has not been recognized yet. S-nitrosothiols provide neuroprotection 124 , protect against amyloid f-peptide neurotoxicity 125 , induce bacteriostatic effect of ax-protease inhibitor 126 , interrupt the replication of the coronavirus 127 , inactivate HIV-1 protease 128 , inhibit dystrophin proteolysis by Coxsackieviral protease 2A 129 , promote expression of the 5-lipoxygenase (5-LO) in several human bronchial cells types 130 and stimulate noradrenalin release in rat brain 81 . Nitrosprusside and SNAP activate a complex extracellular signal-regulated kinase (ERK) pathway via an as yet unknown mechanism 131 . S-nitrosothiols are often found to in uence the life cycle of viruses, for example human immunode ciency 132 , Herpes Simplex 2 and Epstein-Barr 133 . In many cases the mechanism has not been...

The haemophagocytic syndrome (HPS) is characterized by proliferation of macrophages in the bone marrow, spleen, liver and lymph nodes, with inappropriate phagocytosis of erythroid precursors, granulocytes and platelets. In some variations, the skin may be involved. It may occur in severe systemic infections such as cytomegalovirus (CMV), fungal infection and tuberculosis. Clinically, the patient presents with persistent fever, pancyto-penia, jaundice and evidence of liver dysfunction, often with a coagulopathy. The manifestations may be acute or subacute, with the patient exhibiting severe malaise, weight loss and rapidly developing pancytopenia. The jaundice in part is the

OC is a highly conserved bone y-carboxyglutamic acid protein that has been shown to be transcriptionally regulated by 1,25-dihydroxyvitamin D3 (77). This noncollagenous bone protein constitutes 1 to 2 of the total protein in bone, and its expression is limited to differentiated osteoblasts and osteotropic tumors, especially primary and metastatic prostate cancer (78). The osteoblastic nature of osseous prostate cancer metastases is well-characterized (79), and the mechanism is thought to be via its osteomimetic properties, specifically, its ability to express bone-related proteins such as OC (80). The human OC promoter contains numerous regulatory elements, including a vitamin D-responsive element, making it inducible by vitamin D3 administration (81,82), a glucocorticoid response element, an AP-1 binding site (83), and an AML-1 binding site, which has been shown to be responsible for 75 of OC expression (84). The OC promoter retained its tissue-specificity in a recombinant OC...

There are two main types of graft failure seen in aplastic anaemia transplantation. Primary failure is probably related to the disease in that these patients never show any evidence of engraftment. No neutrophils or reticulocytes are seen in the peripheral blood post graft. These patients have a poor outlook and second transplants are usually unsuccessful. Secondary failure occurs after some evidence of engraftment and is probably a true immunological rejection event, although it should be remembered that reactivation of cytomegalovirus infection will also lead to a fall in blood counts. Autologous recovery may still take place, providing that the patient is kept fully supported. Second transplants from the same or another sibling donor have a success rate of about 25 .

Adams et al. used BLI to demonstrate metastasis ofprostate cancer by employing a prostate-specific adenovirus vector, AdPSE-BC-luc 56 . Endocrine therapy is the current treatment for prostate cancer. It involves androgen ablation, but the disease typically relapses within 18-36 months. Viral-mediated gene therapy is a potential alternative to existing treatments. Strong constitutive promoters such as cytomegalovirus (CMV) have high expression but lack specificity. Hence, enhancing the specificity of such constructs can offer additional advantages. In this study, the authors developed a viral construct driven by an enhanced prostate-specific antigen (PSA) promoter. The construct was 20-fold more active than the native PSA promoter and exhibited enhanced specificity and restricted expression. The virally mediated gene therapy concept was tested in scid mice that were implanted with several human prostate cancer models (LAPC series). They observed that their vector transduced the...

Antibodies directed against herpes virus types 1 and 2 could be used in order to increase the sensitivity of making a diagnosis of herpetic dermatitis in cases without blisters or vesicles (Fig. 1A,B). In some cases, antibodies detect the viral antigens, although morphologic changes of herpetic infection of keratinocytes and within nerves cannot be observed (1,2). Tzanck smears and direct immuofluorescence tests performed on cytologic preparations are thought to have a higher sensitivity in establishing a diagnosis of herpes infection than do tissue sections stained with anti-herpes virus antibodies. However, these techniques cannot reliably distinguish between herpes virus types 1 and 2 (3,4). In recent years, specific antibodies directed against herpes virus types 1 and 2 have been developed, permitting distinction between these organisms that cannot be made on routine histologic sections (4). As lesions age, herpes antigen load diminishes, lessening the likelihood of a positive...

Antibodies directed against the herpes family viruses are widely available. These antibodies recognize epitopes that survive routine processing and are useful in detecting the present of herpes virus particles in the skin. There is still some concern about extensive cross reactivity, however, and in most cases, it is not yet advisable to attempt to distinguish type 1 from type 2 herpes based upon immunostaining results. Anti-herpes antibodies do not require pre-treatment with enzymatic digestion or HIER.

Abnormalities of this delicate and complex interplay between the fetal and the maternal immune systems and infections can result in fetal compromise, maternal or fetal death, or pre-term birth. Although the mechanism is not well understood, many data support the association between subclinical infection and preterm birth (see Chapter 9). Infections with the rubella virus, cytomegalovirus, Toxoplasma, the syphilis spirochete, the malaria parasite, and human immunodeficiency virus during pregnancy can have devastating consequences for the fetus and infant (Beckerman, 2005 Pan et al., 2005 Sanchez and Ahmed, 2005). Other maternal infections and subsequent inflammation in the fetus have been implicated as causes of fetal brain injury (including white matter injury, neuronal cell disruption, and programmed neuronal cell death) and, later, neurodevelopmental disabilities (Dammann et al., 2002 Hagberg et al., 2005 Walther et al., 2000).

At present, the treatment of advanced and metastatic medullary thyroid carcinoma is unsatisfactory. Novel alternative therapeutic approaches are under investigation and several experimental studies are already ongoing 173 . Tissue-specific cancer gene therapy has been evaluated for several years. Adenovirus-mediated tumor-specific combined gene therapy using the herpes simplex virus thymidine ganciclovir system and murine interleukin-12 seems very promising. An effective growth suppression of tumor has been observed in rat models affected by medullary thyroid carcinoma and treated with this system 174 . Other interesting approaches are based on immunotherapy, for example stimulation of immune response and vaccination with tumor lysate 175,176 .

Chlamydia, herpes virus and other pathogens are presumed to injure blood vessels Ross, 1999 . Postprandial hypertriglyceridemia is also proposed to trigger the vessel injury (fig. 75, 76). Advanced glycation endproducts (AGE) may also trigger endothelial injury (fig. 81). Inflammatory reactions would follow to repair the injury. When LA intake is high and membrane phospholipids are saturated with AA, the enhanced LA cascade leads to persistent inflammation by over- and unbalanced production of eicosanoids (elevated TXA2 PGI2 ratio and increased leukotriene production). Increased thrombotic tendency leads to ischemia and inflammation. Reactive oxygen species produced by hypoxic (ischemic) mitochondria and or inflammatory cells attack LDL to form oxidized LDL, stimulate cell-proliferation and thereby accelerate atherogenesis. The lipid factor I in this figure is associated with 6 3 balance and the LA cascade.

Fluorescence anisotropy decay microscopy was used to determine, in individual living cells, the spatial and temporal monomer-dimer distribution of GFP-tagged herpes simplex virus thymidine kinase (TK). Measurement of the rotational time of the proteins by confocal microscopy and a time-correlated single photon-counting technique allowed the determination of their oligomeric state in both the cytoplasm and the nucleus. It was demonstrated that tagged TK was initially produced in a monomeric state and then formed dimers that grew into aggregates. Picosecond time-resolved fluorescence anisotropy microscopy was thus proposed as a promising technique for obtaining structural information on proteins in living cells, even in the case of low protein expression levels (Gautier et al. 2001).

Record with them in case of an emergency and or to get general advice in transit or at the destination. This should include a recent evaluation by the women's health clinician. The following should be included gestational age, presence of an intrauterine pregnancy on ultrasound, fetal growth performance, and appropriate medical and obstetric history. Laboratory data should include blood type and Rh factor. Serology for toxoplasmosis, rubella, measles, chickenpox, cytomegalovirus and hepatitis B should also be considered, if not done previously.

The herpes simplex virus PCR assay initially used in our laboratory was the LightCycler hybridization probe method originally described by Espy et al., (2000), using an asymmetric primer concentration for the improved resolution of melting temperatures (Protocol 2). Briefly, the assay targets the herpes simplex virus DNA polymerase gene and works on the basis that both hybridization probes are complementary to target sequences on the herpes simplex virus type 2 DNA genome. However, one of the probes has two mismatches with herpes simplex virus type 1 DNA target sequences, thereby theoretically lowering the melting temperature for herpes simplex virus type 1 by approximately 7 C. In applying this method we found that the majority of our local herpes simplex virus strains can be differentiated as herpes simplex virus 1 or 2, but that approximately 5 of herpes simplex virus positive specimens produce melting temperatures that are not characteristic of either the type 1 or 2 melting...

Quantitative PCR analysis of viral nucleic acid is now used by diagnostic laboratories worldwide and is particularly useful for monitoring viral loads in patients to assess the effect of anti-viral therapy and potentially to detect drug-resistant viral strains. In clinical virology, qPCR is commonly used for the detection and quantification of blood-borne viruses, including hepatitis B and C and human immunodeficiency viruses. However, it is also increasingly used to monitor viral pathogens of transplant patients, including Epstein-Barr virus, cytomegalovirus and BK virus. In recent years, our laboratory has used quantitative real-time PCR to investigate BK viral loads in a transplant patient population (see Protocol 14.3). BKV can cause several clinical manifestations in immunocompromised patients including hemorrhagic cystitis and allograft nephropathy. Since adopting qPCR, several limitations of this technology have been identified, including the impact of PCR inhibitors, poor...

In qPCR applied to clinical virology, the main sources of error include the nucleic acid isolation process and the presence of PCR inhibitors in clinical specimens. In our opinion, the best way to control for these factors is by using an internal control strategy previously described by Niesters (2004). Briefly, this involves spiking specimens and standards prior to extraction with a known concentration of an unrelated virus, in this case seal herpesvirus (PhHV-1), which is then extracted with the test specimen. The specimen extracts are subsequently each tested by a PhHV-1 TaqMan assay and the Ct values compared to a predetermined range of Ct values. Specimens providing Ct values for PhHV-1 that are outside this expected range are then repeated (Protocol 14.4). The benefit of this approach is that it simultaneously controls for both the presence of PCR inhibitors as well as inefficiencies in the extraction protocol. Further, the extraction of the seal herpesvirus is more...

The concentration of seal herpesvirus (PhHV-1) added to each patient specimen should be sufficient to provide an average Ct value of approximately cycle 30 in a correctly extracted sample containing no PCR inhibitors. This equates to a final concentration of approximately 5,000 copies per mL of specimen. Briefly, 10pL of PhHV-1 at 500 copies per pL should be added to 1mL of each specimen. LightCycler melting curve analysis for two herpes simplex virus type 2 positive specimens showing uncharacteristic melting temperatures compared to a herpes simplex virus type 2 positive control. The results were obtained using a hybridization probe-based assay targeting the DNA polymerase gene. Troubleshooting guide 14.3 Uncharacteristic herpes simplex virus type 2 melting curves Two herpes simplex virus (HSV) type 2 positive specimens providing uncharacteristic melting curves were further investigated to identify the cause of the shift in melting temperature. Briefly, PCR products from these...

At least four of the regulatory complex ATPases (S6, S6', S7, and S8) have been linked to transcriptional control by the Tat protein of the human immunodeficiency virus, yeast Gal4, the herpes virus activator VP16, or the thyroid-hormone receptor.64-71 Evidence has been presented that the yeast homologue ofS8, Sug1, is not present in the 26 S proteasome but rather associates with the RNA polymerase II holoenzyme complex or the TATA-box binding protein.69'72 Subsequent reports have, however,

Viral pathogens have emerged as the most important microbial agents having deleterious effects on solid organ transplant recipients. Antiviral chemoprophylaxis involves the administration of medications to abort transmission of, avoid reactivation of, or prevent progression to disease from, active viral infection. Real-time PCR amplification techniques are currently used to determine the viral load in clinical samples for an increasing number of targets, and in a short turn-around time, and to determine whether variants relevant for antiviral resistance are present (see, for example, Chapter 14). Technological improvements, from automated sample isolation to real-time amplification technology, have given the ability to develop and introduce systems for most viruses of clinical interest, and to obtain clinical relevant information needed for optimal antiviral treatment options. Treatment initiation is based not only on the viral load itself but also on a combination of difference...

As previously noted, the milieu of potential metastatic sites plays a major role in the ability of a cancer cell to multiply, utilize angiogenesis, and avoid the immune system to survive and form metastases. Bone is the best-studied system because of the proclivity of prostate cancer to metastasize skeletally. Prostate cancer cells have osteomimetic properties, which are likely to support metastasis within the bone environment and reciprocal interactions between prostate cancer, and bone stromal growth factors leading to gene expression of osteopontin (OPN), osteocalcin (OC), and bone sialoprotein (BSP) may occur. Furthermore, prostate cancer metastases in the bone are frequently osteoblastic and likely due to the secretion of soluble factors by prostate cancer cells, which stimulate bone production.147 In the mouse model, the prostate cancer cell line PC-3 localized preferentially to human bone implanted in the hindlegs, specifically to the reconstituted...

The first report to demonstrate anticancer activity of gene therapy in human prostate cancer, by Herman and colleagues, used intratumoral injection of replication-deficient adenovirus carrying the thymidine kinase gene from the herpes simplex virus, followed by parenteral administration of the prodrug gancyclovir. They report promising results with some patients with local recurrence after radiotherapy obtaining a greater than 50 decrease in PSA lasting 6 weeks to 1 year.180 These data support the usefulness of cytoreductive gene therapy, by 'suicide' genes, or by increasing tumor cell sensitivity to chemotherapeutics. Replication-deficient adenovirus containing the herpes simplex virus thymidine kinase (HSV-tk) gene ('suicide' gene therapy) has also been used in men with localized prostate cancer. Multiple and or repeat intraprostatic injections was followed by intravenous ganciclovir or oral valaciclovir 14 days after injection. A total of 52 patients were treated, with a total of...

And the herpes simplex vims (HSV) protein VP 16 activation domain. This mutated HBD does not bind to progesterone or its agonists, but it binds to the progesterone antagonist RU486 (Mifpristone) with high affinity. The reporter contains multiple GAL4 binding sites (17-mer) and a promoter driving the expression of a target gene. With this novel approach, we transformed a constitutive transactivator GAL4-VP 16 into a RU486 regulatable transactivator GL-VP. In the absence of RU486, this chimeric regulator (GL-VP) will not bind to the 17-mer sites present on the reporter. Hence, little or no expression of target gene transcription will occur. However, upon binding to RU486, a conformation change is effected in the regulator GL-VP, enabling the regulator to bind to the 17-mer GAL4 binding sites on the target gene construct and thereby initiate the transcription of the target gene. We have recently demonstrated that this inducible system works in transient transfection assays as well

An important aspect of gene therapy is the gene delivery system, i.e., the transfer of therapeutic genes to various human tissues. There are a number of techniques available for ex vivo gene transfer in human cell lines like chemical transfer (calcium phosphate precipitation) (97) and liposome-mediated gene transfer (98) For in vivo gene therapy, the most promising options are the physical gene transfer involving microinjection (1) and viral vectors. The viral vectors include retroviruses, adenoviruses, adeno-associated viruses, and herpes simplex virus. Viral vectors differ in their nature, which affects the expression of the gene being delivered. For example, retroviral vectors stably integrate into host genome, whereas adenoviral vectors exhibit broad host range, efficient infectivity, including nondividing cells Moreover, adenoviral vectors have low genotoxicity in host cells due to episomal expression. The use of herpes simplex virus vectors is not well established (99,100)....

Herpes simplex virus viral vectors have focused on four major groups of viruses Retrovirus, Adenovirus, Adeno Associated Virus (AAV) and Herpes Simplex Virus (HSV). Each of these is discussed in the following sections. Adeno-associated viruses (AAV) are non-pathogenic satellite viruses of other human viruses and require co-infection with either adenovirus or herpes simplex virus (HSV) for their replication 21, 22 . A unique feature of the DNA molecule contained within the virion is the presence of inverted terminal repeat (ITR) at both ends. These ITRs are important in the site-specific integration of AAV DNA into a specific site in human chromosome 19. The ability of wild-type AAV to selectively integrate into chromosome 19 makes them attractive candidates for the production of a gene therapy vector. For production of virus vectors, cells are first infected with the wild-type adenovirus or HSV and then both the recombinant AAV vector plasmid DNA and the non-rescuable AAV helper...

In a mouse or hamster cell line, murine retroviruses detected in the cells or unprocessed bulk are one of the main virus groups of concern, since a very small proportion of these retroviruses have been shown to be capable of replicating, although none of these have been shown to be capable of infecting human cell lines. Therefore a model for a murine retrovirus must always be included in any study and murine leukemia virus (MuLV) is most commonly used as a model specific virus. Pseudorabies virus is a model for a herpes

Include other brain diseases (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis), psychiatric disorders (e.g., schizophrenia, depression), substance abuse (e.g., alcohol, cannabis, MDMA), viral infections (e.g., HIV and Herpes Simplex Encephalitis), and developmental disorders (e.g., ADHD, autism). The patient groups were chosen in these studies mainly because they were reported to have prospective memory problems or because their pathology is related to brain areas that are supposed to be related to prospective memory. Most of these studies compared the performance of clinical groups and matched controls on one or more types of prospective memory (e.g., time-, event-, or activity-based) using tasks developed in the experimental literature. Typically, the results of these studies indicate that these patients tend to be impaired on one or more types of prospective memory (refer to Table 13.1).

The greatest successes with nucleoside drugs have been in the treatment of leukemias, lymphomas, HIV, and herpes virus infections. These drugs act intracellularly after conversion to nucleotide phosphates, generally by blocking DNA synthesis. Although nucleoside transport is important, the limiting step that defines the activity of nucleoside drugs

In a similar vein, hyperbole (308-338) masked the true incidence of complications. Some cautious but perhaps courageous laser surgeons did report side effects and preached thoughtful reflection and methodology (222,319,349,355,462-469). This author raised the question of underreporting of scarring and the role of wound dressings in preventing hypertrophic scarring in 1984 (75). In a 1987 review Olbricht et al. (463) surveyed laser surgeons, 69 of whom had seen at least one case of hypertrophic scarring after argon laser and 64 after CO2 laser surgery, but no true incidence of scarring was tabulated. Lent and David (464) noted hyperpigmentation in 16 of laser-resurfaced patients postoperatively and Fitzpatrick et al. (319), 25 . Nanni and Alster (466) found a 37 incidence, more common in darker patients (up to 100 of Fitzpatrick type IV and V patients) (355,466), but this is reversible particularly with postoperative hydroquinones. Bernstein et al. (349) first made known the previously...

Depletion of cellular polyamines dramatically inhibits c-myc gene transcription and decreased levels of c-Myc protein (39,41,42), which is associated with a significant reduction of E-cadherin promoter activity in IEC-6 cells (40). We have successfully constructed the adenoviral vector containing c-Myc cDNA (AdMyc) under the control of the human cytomegalovirus immediate early gene promoter. Infection of IEC-6 cells with AdMyc vector increased c-Myc protein by approx 20-fold, and this forced expression of the c-Myc stimulated transcription of the E-cadherin gene as indicated by a significant increase in E-cadherin promoter activity. The level of E-cadherin-promoter activity was increased by approx threefold when cells were infected with the AdMyc at

When diagnosing dissociative amnesia and fugue, a number of other disorders and conditions have to be excluded. A number of medical conditions such as vitamin deficiency, head trauma, carbon monoxide poisoning, and herpes encephalitis can produce similar symptoms. Amnesia can also be found in conjunction with alcoholism and the use of other drugs.

Several infectious agents have been proposed as possible etiologic factors in the development of vulvar carcinoma, including various granulomatous infections, herpes simplex virus and human papillomaviruses (HPV). The molecular role of the human papillomavirus in cervical dysplasia and carcinoma as well as the association between viral induced vulvar condylomata and subsequent development of vulvar carcinoma has been well established.7 Many investigators have identified HPV DNA in both invasive and precursor carcinoma in situ vulvar lesions.8 With the increasing incidence of HPV related dysplasias in the younger female population and the reported trend toward a younger age of diagnosis9 there is certainly cause for concern that an increase in related vulvar cancer may be forthcoming. In a study by Mitchell et al10 169 women with invasive vulvar carcinomas were noted to have a secondary genital squamous neoplasm in 13 of

Apart from helping to elucidate the cause of the epiphora, the history (Box 10.2) allows assessment of the degree of functional disturbance to the patient. In some, epiphora is simply a mild nuisance, whereas in others it significantly interferes with their quality of life, often with a profound effect on reading and driving. In most cases tears spill over at the medial canthus, whereas lateral spillover usually occurs with lower lid laxity (Figure 10.11). The nature of the discharge, whether water, mucus, pus or blood-stained tears, is a useful guide to the likely type of block bloodstained tears, although most commonly due to severe Actinomyces canaliculitis, may indicate a tumour of the lacrimal drainage system. Bilateral epiphora associated with itching, foreign body sensation, pain or photophobia is indicative of reflex hypersecretion. Obstructive epiphora is often unilateral and usually worse outdoors in cold, windy conditions. A history of cicatrising conditions such as...

The hallmark of chronic rejection in liver recipients is biliary ductular necrosis, termed ductopenia and vanishing bile duct syndrome, which results in progressive jaundice. The ducts suffer direct lymphocytotoxic injury as well as ischemia from the obliterative vasculopathy caused by antibody-mediated intimal damage of hepatic arterioles. In the late phase of chronic rejection there is diffuse hepatic fibrosis. Allograft function deteriorates, marked by cholestasis and ultimately, loss of synthetic function and portal hypertension. Putative risk factors include human leukocyte antigen (HLA) mismatching and nonimmunologic factors such as ischemia reperfusion injury and cytomegalovirus infection. Heavy immunosuppression with tacrolimus, mycophenolate mofetil, and or sirolimus may reverse chronic rejection in the early phases. Advanced chronic rejection is an indication for retransplantation. Commonly observed in the first 6 months posttransplant, duodenal-bladder leaks can be seen in...

As described in Chapter 4, oligopeptide and mono-carboxylic acid transporters facilitate the absorption of certain drugs. There have been a number of demonstrations that these natural transport pathways can be exploited to enhance drug action. An example demonstrating this concept is the discovery that valacyclovir is a substrate for the PEPT-1 transporter (81). Valacyclovir is an amino acid ester prodrug of the antiviral drug acyclovir. The usefulness of acyclovir is somewhat limited by its poor bioavailability. However, the oral bioavailability of valacyclovir is increased three- to fivefold in humans. Experiments using a rat intestinal perfusion model demonstrated a 3- to 10-fold increased intestinal permeability of valacyclovir over acyclovir. The effect was specific (i.e., exhibited structure-activity preferences among a family of amino acid ester prodrugs), and was stereospecific for l-valine, saturable, inhibitable by known PEPT-1 substrates (cephalexin, dipeptides), and...

The third study determined the effect of overexpression of the junD gene on p21 promoter activity and cell proliferation in Caco-2 cells. When cells were transfected with the expression vector containing the human junD complimentary DNA under the control of human cytomegalovirus immediate-early promoter (PMCV), levels of JunD protein were increased by approximately sixfold at 24 h and by approx 14-fold at 48 h after the transient transfection, respectively. The vector that lacked exogenous junD co mplime ntary DNA (null) was used as a negative control and did not induce JunD levels. Overexpression of the junD gene significantly activated the p21 promoter. The activity of p21 promoter luc iferase reporter was increased by approximately eightfold 48 h after the transfection. The increased JunD by the transfection also inhibited Caco-2 cell proliferation. Cell numbers were decreased by approx 25 at 48 h and approx 38 at 72 h after the transfection. These results indicate that increased...

According to some studies 149 , but not all 150 , a positive association exists between tobacco smoking and CRC. Also, occupational exposure to some chemicals (asbestos and some organic solvents) showed an increased risk 151 . Recently, it has been suggested that cytomegalovirus infection may play a role in the development of CRC 152 .

OC is a highly conserved bone gamma-carboxyglutamic acid protein (BGP) that has been shown to be transcriptionally regulated by 1,25-dihydroxyvitamin D3.16 This noncollagenous bone protein constitutes 1-2 of the total protein in bone, and its expression is limited to differentiated osteoblasts and osteotropic tumors.17 Figure 1 depicts expression of OC RNA and protein in primary and metastatic prostate cancers. The osteoblastic nature of osseous prostate cancer metastases is well charac-terized,18 and the mechanism is believed to be via its osteomimetic properties, specifically its ability to express bone-related proteins such as OC.19 The human OC promoter contains numerous regulatory elements including a vitamin D-responsive element (VDRE), making it inducible by vitamin D3 administration,20,21 a glucocorticoid response element (GRE), an AP-1 binding site,22 and an AML-1 binding site which has been shown to be responsible for 75 of OC expression.23 The OC promoter retains its tissue...

Many dermatoses may be provoked by exposure to ultraviolet (UV) radiation and they may be acute or chronic. In addition, a number of other dermatoses may be exacerbated by exposure to sunlight these include acne, atopic eczema, dermatomyositis, erythema multiforme, herpes simplex, Darier disease, lichen planus, autoimmune blistering disorders, psoriasis, rosacea, and seborrhoeic dermatitis. Some of the more common problems included in this section are presented in Table 9.4.

Thrombocytopenia may result from continued splenic sequestration, drug toxicity (furosemide, mycophenolate), infections (herpes, parvovirus, sepsis syndrome), preformed antibodies, and rejection. Usually it is safe to allow a platelet count of 20,000 as long as there is no bleeding. With a well-functioning graft, thrombocytopenia should resolve within 1 week. Most viral infections occur between 3 and 4 weeks postoperatively. However, up to 10 of infections in the immediate postoperative period are viral in nature. Reactivation of cytomegalovirus (CMV) is a major cause of viral infection. CMV syndrome is manifested by fever, myalgia, malaise, leukopenia, and thrombocytopenia. The liver allograft is the most common site of organ involvement. Treatment and prophylaxis with immune globulin preparations, gancyclovir (IV and by mouth), and or acyclovir are extremely effective. This regimen should last approximately 100 days.

Transplantation, and concomitant drug therapy. Medications used to prevent and treat the unwanted effects of immunosuppression should be chosen carefully, because these medications often interact with immunosuppressive agents. These interactions can often be exploited, however, by using lower doses of immunosuppressants. Some patients are more prone to the effects of immunosuppression than others for instance, a recipient patient who lacks antibodies to cytomegalovirus (CMV) and receives an organ from a CMV-positive donor is more likely to develop symptomatic CMV than a recipient patient who has CMV antibodies. Finally, patient adherence and compliance to regimens are extremely important, and nonadherence is a common cause of organ rejection. Multidisciplinary transplant teams work collaboratively with patients to increase compliance with complicated medication regimens. Important Drug Interactions. Acyclovir, gancyclovir and trimethoprim-sulfamethoxazole (Bactrim increased...

Being obligate intracellular parasites, viruses are dependent on the metabolic pathways of the host cell for their replication. So, virus and host cell are intimately connected and an effective antiviral agent must be able to distinguish virus related enzymes from host cell material itself. The search for antitumour agents generated a great deal of interest in DNA synthesis inhibitors. The first drugs capable of inhibiting viral DNA in vitro were described in the 50s, but real progress was not made until the 70s. In the last decades we have come to know more about the biochemistry of viral replication and this has led to a more rational approach to the search for antiviral agents. When reviewing the possibilities for antiviral chemotherapy, the best guideline is the viral replicative cycle, which can be divided in ten steps (Figure 1). First a virus binds to the cell surface of the host cell and penetrates the cell membrane and shed its protein coat (1-3 binding and entry). The...

Positron yield of 18F is preferred, and other applications in which the longer half-life of 124I is desirable. Further details of various issues surrounding the substrates for HSV1-tk can be found elsewhere 87 . We have also investigated a mutant HSV1-tk reporter gene (HSV1-sr39tk) that has six point mutations, which leads to a HSV1-sr39tk enzyme with better imaging sensitivity when using FGCV and FPCV, as compared to the wild-type HSV1-tk 98 . This enzyme was isolated by screening a library generated by site-directed mutagenesis of the HSV1-tk gene with acyclovir and ganciclovir 99 . This mutant enzyme also has the distinct advantage of having a lower phosphorylation rate for thymidine, which directly competes with various substrates (for example, penciclovir, FHBG) for HSV1-tk HSV1-sr39tk. This is important because levels of thymidine can vary and confound the imaging signal independent of changes in reporter gene expression 100 . Future HSV1-tk mutant reporter genes that have been...

Progressive hearing impairment has been reported in infants with cytomegalovirus infection and persistent pulmonary hypertension of the newborn. These infants and infants who demonstrate a delay in language milestone acquisition should have a follow-up hearing test during the first year of life.

The use of antisense technology has been applied to a number of diverse organisms, including Drosophila melanogaster, plants, and mammals. The purpose is to take advantage of the base-pair specificity of both RNA RNA and RNA DNA interactions, ultimately to block protein production. This technique requires the production of exogenous antisense mRNA, generated either constitutively or inducibly, from a functional promoter. Classically, a constitutive promoter, such as the cytomegalovirus (CMV) promoter, is utilized to express high levels of antisense mRNA. This mRNA then binds irreversibly to endogenous sense mRNA, thus preventing its efficient translation, which results in attenuation of the protein product. Synthetic antisense oligo-nucleotides are also commonly used for constitutive antisense targeting. These DNA oligomers bind to endogenous RNA to generate RNA DNA hybrids that are targeted by RNase H and degraded. This method will not be described at length in this chapter. In order...

Several patients with Herpes encephalitis were studied by Bell et al. 53 and the relative specific antibody (RSA) is given in Table 10.7 which shows the effect of integrating the area under the curve for the total amounts of IgG in CSF and parallel serum to give one quotient. A second quotient is calculated by the division of the area under the curve for the antigen-specific (in this case herpes simplex) antibody TABLE 10.7 Measures of herpes-specific and total IgG TABLE 10.7 Measures of herpes-specific and total IgG

The majority of patients with SCID present with severe persistent infection in infancy or early childhood. A typical scenario is failure to thrive during the first 2 years of life, episodes of protracted diarrhoea and persistent cough due to an opportunistic fungal respiratory infection (Figure 22.1). However, there are many exceptions to this 'classical' presentation, some patients having features that are not directly related to infection, such as skin rashes, severe autoimmune phenomena, lymphadenopathy and hepatosplenomegaly. The associated antibody deficiency leads to a susceptibility to bacterial infection, particularly with Haemophilus influenzae, pneumococci and enteric pathogens such as Campylobacter jejuni. The cellular immunodeficiency leads to chronic fungal infections that are often difficult to diagnose and treat, such as Pneumocystis carinii, Aspergillus fumigatus and Candida albicans chronic viral infection is also common, particularly rotavirus enteritis and...

The diagnosis and course of IM are usually uncomplicated. Signs of significant respiratory, cardiovascular, intestinal, urinary or joint disease make consideration of other diseases mandatory some of these other diseases are listed in Table 20.7. Perhaps the commonest problem is when the patient is heterophile antibody negative. In this situation, other viral infections, particularly cytomegalovirus (CMV), should be considered, with assay for CMV-specific IgM. Primary EBV infection is rare in older patients and there may not be conspicuous lymphadenopathy. Occasionally, the blood picture may raise the suspicion of a leukaemia, in which case immunophenotyping of the blood mononuclear cells may be appropriate. Persistent lymphadenopathy beyond a few weeks suggests the need for diagnostic biopsy, particularly if heterophile antibodies are negative, but also the possibility of a false-positive Monospot test should be considered. Virus-specific serology may be helpful in both these...

Fig. 2. pGFP-C 1, pRSGFP-C 1, and pS65T-C1 plasmid map Each of these vectors can be used to express GFP, or the corresponding GFP variant in mammalian cells. The vectors also permit genes cloned into an MCS at the end of the coding sequences to be expressed as fusions to the C-temiinus of GFP or GFP variants. GFP, GFP variants, or fusion proteins are expressed under control of the immediate early promoter of cytomegalovirus (Pcmv ie)- An upstream Kozak consensus sequence (72) and a downstream SV40 polyadenylation signal direct proper processing of mRNA in eukaryotic cells. The vector backbone also contains an SV4Q origin for replication in mammalian cells expressing the SV40 large T antigen. A neomycin-resistance cassette allows for G418 selection of stably transfected eukaryotic cells. A bacterial promoter (Pamp) expresses kanamycin resistance in E. coli. The backbone also provides a pUC 19 origin of replication for propagation in E. coli, and an fl origin for single-stranded DNA...

The profound functional diversity of heparan sulfate (HS) proteoglycans is largely engendered by the regulated structural complexity of the glycosaminoglycan (GAG) component (reviewed in ref. 1). Ultimately, the status of the heparan sulfate biosyn-thetic machinery dictates fine structure that encodes binding sites for protein ligands. In part, regulation of fine structure is made possible through the existence of multiple isoforms for most of the HS sulfotransferases (2,3). Examination of the heparan sulfate 3-0-sultotransferase (3OST) family shows that each isotype exhibits a unique sequence specificity (4). All 3OST enzymes place a sulfate group in the 3-0-position of glucosamine residues within heparan sulfate however, each isoform recognizes and modifies a distinct sequence context. Consequently, only 3OST1 generates the antithrombin-binding site, whereas 3OST3 makes binding sites for gD, an envelope protein of herpes virus (4,5). The existence of a multitude of sulfotransferases...

The efficacy of this approach depends on the conversion of a non-toxic pro-drug to an active cytotoxic drug by the enzymatic product of a delivered gene not normally expressed in human cells. Following systemic administration of the pro-drug, high concentrations of the lethal metabolite are only found locally at the tumor site, avoiding systemic toxicity. Fortunately, the toxic effect is not limited to the cells that produced the cytotoxic drug, but extends to neighboring cells via the bystander effect. This bystander effect is mediated by intercellular gap junctions and phagocytosis of debris from dying cells. By these means, the cytotoxic effect is amplified, compensating for low gene transfer efficiencies. The most widely applied pro-drug gene therapy in prostate cancer utilizes thymidine kinase from the herpes simplex virus (HSV-TK) and any one of several anti-herpetic agents such as ganciclovir (GCV), acyclovir (ACV), or valacyclovir (VAL). These nucleoside analogues are...

Infection in the form of herpes zoster from latent infection. The disease is usually notifiable, the main interest being in investigating cases and outbreaks to exclude smallpox. Infected persons may be isolated from other susceptibles. New antiviral agents, viradabine and acyclovir, are effective in the treatment of zoster and immunocompromised patients.

Acyclovir and valaciclovir which have limited water solubility were coupled with 1.5 kDa PEG-ala-acid to give an ester prodrug which was water soluble and stable in PBS buffer at pH 5.5. The native drugs were released when treated with human plasma. Because of the LMW of the conjugate in vivo testing was not done, but in vitro results in human plasma demonstrated a t1 2 of about 2 h (Zacchigna et al., 2002).

Chest wall lesions (following chest surgery, herpes zoster, nipple piercing) as well as prolonged nipple stimulation can increase serum PRL levels as well as cause galactorrhea. This occurs via a reduction in hypothalamic dopamine. Notably, routine breast exams are not associated with increased PRL. Chronic renal failure, due to a decreased clearance of PRL, can result in hyperprolactinemia. Renal transplant reverses it. Forty percent of patients with hypothyroidism have mildly elevated PRL levels, due to the increase in thyroid releasing hormone, which is also a PRL releasing factor. Some rare causes of ectopic hyperprolactinemia include small cell carcinoma of the lung as well as colorectal cancer. Liver cirrhosis can also cause an elevation of PRL, possibly secondary to decreased clearance.

A direct role for CREB in mediating OD plasticity was tested using viral vector approaches in the ferret V1 (Mower et al., 2002). In these experiments, authors intracortically infused herpes simplex viruses to infect V1 neurons with a double-negative insert for CREB (m-CREB) that blocks its activation

The first antisense drug to be approved (ISIS Pharmaceutical Inc.) was for the treatment of cytomegalovirus retinitis in patients with AIDS. The route of administration of this drug is unique direct intraocular injection. While this does deliver sufficient drug to the appropriate site, it illustrates well the ADME problems associated with antisense drugs.

Neurologic complications occur in 12-20 of patients after liver transplantation. Eighty-five percent of these complications occur in the first postoperative week. The symptoms and signs range from seizures to disorientation, to agitation, to coma, and are more likely in older patients and those with severe encephalopa-thy preoperatively. The causes include toxic-metabolic processes, hypomag-nesemia, hypoglycemia, hypercalcemia, hypo- and hypernatremia (central pon-tine myelinolysis), poor graft function, drug reactions, infections, and intracranial hemorrhage. Medications should be carefully reviewed in order to identify agents that may be the cause of the neurologic changes. These include amantadine, cyclosporine, steroids, narcotic analgesics, histamine type 2 blockers, acyclovir, antibiotics (e.g., Imipenem), benzodiazepines, and tacrolimus. There should be a low threshold for obtaining blood, urine, and sputum cultures, and a computerized tomographic (CT) scan of the head and an...

To date, we have used hybridization probe protocols coupled with melting curve analysis for the routine detection and differentiation of herpes simplex virus (HSV) types 1 and 2 and human polyomaviruses JC and BK (JCV and BKV). Overall, the assays have high clinical sensitivity and specificity. However, two limitations have become evident. First, sequence variation within the viral types can interfere with virus characterization, and second, the assays can fail to detect one viral type when both are present in a single sample (Whiley and Sloots, 2005a).

Packaging system The packaging functions are provided by both the HXBAPlAenv plasmid and the CMVAPlAenvpA plasmid that express the HIV-1 gag, pol, vif, and tat genes The CMVAPlAenvpA plasmid was constructed recently by replacement of the HIV-1 5'LTR on the HXBAPlAenv plasmid (16) with the cytomegalovirus (CMV) immediate-early promoter. (Briefly, the HXBAPlAenv plasmid was partially digested with CM which recognizes a site in the sequences flanking the 5'LTR and Bss HII nucleotide 257 , located

Ever, they are at increased risk for opportunistic infections. The usual viral culprits are DNA herpes viruses, most importantly cytomegalovirus, and also Epstein-Barr virus, herpes simplex virus, and varicella. Cytomegalovirus may present with fever, malaise, leukopenia, hepatitis, esophagitis, enterocolitis, pneumonitis, or retinitis. Treatment involves immunosuppression reduction and gancyclovir, which is highly therapeutic. The most common fungal infections in transplant recipients include candida, aspergillus, cryptococcus, and histoplasmosis. Risk factors for these opportunistic infections include heavy immunosuppressive regimens, often in the face of allograft dysfunction, and use of broad-spectrum antibiotics. Aspergillosis most often presents with respiratory symptoms, and cryptococcus, most often with meningitis. These fungal infections are treated with fluconazole or amphotericin B, but mortality rates are high. Other opportunistic infections include Pneumocystis carinii,...

The incidence of T-cell lymphoma is also increased but only five- to tenfold. In addition, two uncommon lymphoproliferative disorders that are associated with human herpesvirus 8 are seen in this population primary effusion lymphoma (PEL) or body-cavity lymphoma and multicentric Castleman's disease. Histologically, PEL is a CD30-(Ki-1)-positive anaplastic large cell lymphoma.

Lacrimal canalicular obstructions may rarely be idiopathic, but are generally the result of infection (primary Herpes simplex and zoster, or Actinomyces canaliculitis), trauma (direct, iatrogenic or irradiation), cicatrising mucous membrane diseases (pemphigoid, chronic ocular medication, or topical drug reactions such as StevensJohnson syndrome), or involvement with tumours (papillomas or secondary to skin tumours). With these causes in mind, associated abnormalities should be sought during the ocular examination for example, in the presence of a progressive disease such as ocular pemphigoid, it may be undesirable to place a canalicular bypass tube for fear of

Ganciclovir (dihydrophosphoguanine) is a derivative of acyclovir and is effective when given intravenously in serious cytomegalovirus (CMV) infection, including CMV retinitis. It produces severe bone marrow suppression, especially neut-ropenia, in a high percentage of patients and this is probably worsened by concurrent administration of zidovudine. Valgan-ciclovir, an oral prodrug of ganciclovir, has recently been shown to be as effective for induction treatment of CMV retinitis as ganciclovir, and has a similar degree of haematological toxicity. Oral ganciclovir is less marrow toxic than the intravenous preparation but is ineffective as treatment of CMV though may be useful for prophylaxis.

Cytomegalovirus (CMV) infection, frequently cause marrow suppression. Several clinical trials have now demonstrated the benefit of epoetin therapy in some patients with HIV-associated anaemia. Improvements in Hb and a significant reduction in transfusion requirements have been seen in patients with an Epo level of &lt 500 IU L, whether or not the patient is receiving anti-retroviral therapy.